Fig.14.11 ).Specifically,EDHFappearstobeanarachidonicacidmetabolite(e.g.,epoxyeicosatrienoic acid [EET])thatisproducedbyendothelialcellsinresponsetovariousstimuliandthenreleasedtotheunderlyingvascularsmoothmuscle.EEThasbeenshowntoactivateatransient receptor channel (e.g.,TRPV4)inthesarcolemmaofsmoothmusclethatleadstotheinfluxofCa++ ,whichthenopensRYRchannelsintheSRandresultsinCa++ sparks.TheCa++ sparksinturnactivatealarge-conductanceK+ channelinthesarcolemma(BKCa),andthesmoothmusclecellbecomeshyperpolarized.HyperpolarizationinturndecreasesbasalCa++ influxthroughvoltage-gatedCa++ channelsinthesmoothmuscle,therebydecreasingintracellular[Ca++]andhencerelaxingthesmoothmuscle,asdescribedearlier.
In addition to the InsP3 receptor, the SR also contains the Ca++-gated Ca++ channel, also called the RYR, which may be activated during periods of Ca++ influx through the sarcolemma. Short-lived spontaneous opening of the RYR 11,12 EET COOH •Fig. 14.11 Anarachidonicacidmetabolite(11,12-epoxyeicosatrienoicacid[11,12EET])releasedfromendothelialcellscanopenthetransientreceptorchannelTRPV4intheunderlyingsmoothmuscletopermittheinfluxofCa++ ,whichinturninitiatesbriefopeningsoftheSRryanodinereceptor(Ca++ sparks)localizednearthesarcolemma.OpeningofCa++-activatedK+ channelsinthesarcolemmabycalciumsparksresultsinhyperpolarizationofthesmoothmuscleandhencevasodilation.BKCa,largeconductanceCa++-activatedpotassiumchannel.(FromEarleySetal.Circ Res 2005;97:1270-1279.) resulting in localized elevations in myoplasmic [Ca++] occurs in many cells, including smooth muscle. When observed with Ca++-sensitive fluorescent dyes, these spontaneous localized elevations in myoplasmic [Ca++] produce brief light flashes and as a result are named Ca++ sparks. In smooth muscle an increase in cAMP has been associated with an increase in the frequency of Ca++ sparks, particularly in situations in which the SR is in close proximity to the sarcolemma (i.e., junctional SR, perhaps near caveolae). An increase in the frequency of these sparks hyperpolarizes vascular smooth muscle by activation of a large-conductance Ca++-gated K+ channel in the sarcolemma. This hyperpolarization then decreases overall myoplasmic [Ca++], and relaxation occurs.